PROJECT SUMMARY The DIAN-TU was formed to design and manage interventional therapeutic trials and find a treatment that provides cognitive benefit for those certain to develop autosomal dominant AD (ADAD). The DIAN-TU trial platform successfully launched and completed enrollment for the first two drugs arms (both monoclonal anti- abeta antibodies) in 6 countries (3 languages) and 24 sites, and results will be available in early 2020. In 2017, with the DIAN-TU NexGen grant (R01AG053267, RJ Bateman, PI), the DIAN-TU added a third drug arm (a BACE inhibitor) and implemented key design changes that allow the platform to test additional drugs with diverse mechanisms of action more quickly and efficiently. Significant innovations include implementation of (1) a planned cognitive run-in (CRI) period prior to drug administration, (2) self-administered cognitive testing, (3) a pre-defined dose escalation algorithm to safely maximize target engagement, (4) four plus year cognitive endpoint adaptive trial design which includes biomarker and cognitive interims to inform early efficacy or futility, (5) novel imaging (e.g. Tau PET), and (6) ADAD Disease Progression Model (DPM) to detect changes in cognition earlier. These innovative approaches promise to accelerate identification of effective drugs for prevention and treatment of AD. In 2018, the third drug arm was stopped due to safety concerns. To best utilize the time before launching a fourth drug arm and collect additional pre-randomization data, the DIAN-TU will implement a CRI period prior to randomization for a fourth drug arm. Tau imaging will be included with the CRI to enable better understanding of tau aggregation in ADAD and further validate a new tau tracer (MK-6240, Cerveau). As noted above, a CRI period, which involves enrolling trial-eligible participants to collect cognitive, clinical, and biomarker data prior to randomization, was included in the original grant research plan to take advantage of the intervening time between enrollment completion of the third drug arm and randomization for a fourth drug arm. However, funding for this effort was not included in the grant budget because it was not expected to occur until the end of the grant period. Due to the early termination of the third drug arm, the timelines to launch CRI and a fourth drug arm have been accelerated. In addition, the grant funding was intended to support start-up, launch, and maintenance of a single drug arm. With the expenses of start-up, launch, termination, and close- out of the third drug arm, funds to support a fourth drug arm are now limited. This administrative supplement requests additional funding to support a CRI period with tau imaging and launch a fourth drug arm in accordance with the original grant aims. Implementing a run-in period can improve power, decrease variability in cognitive test performance and practice effects, improve adherence to the trial protocol, and reduce attrition rates. Including tau imaging supports the transition to tau-targeted therapeutics for the fourth drug arm.